Process for the manufacture of diquaternary salts of pyrimidylaminoquinolines



Patented Fel a. 19, 1952 UNITED STATES PATENT oe-Flee 2,585,972 PROCESSwon THE MANUFAGTUREJOE m QUATERNARY s-ALTs F PYRIMIDYLA- MINoQUINotINEshall, Englandfasisi'ginors to Impe ial Chemical Industries Limited, acdfiioratfo'n 6f Great Britain No D w t ibi ii membe 11 ,549, ic.-

pialNo. 125,374. In Great Britain November 2 Claims.

This invention relates to the manufaeturenf quinoline derivatives andmore particularly it relates to the manufactureof diquaternary salts ofpyrimidylamino-quino1ines possessing trypanocidal activity.

The compounds with the manufactiire of which this inventionis'concernedmay be formulated PciNHQq wherein P stands for a2-m;1'1rio"- er 2- lower alkylar'ni'nmsiibstituted pyrimidine nucleus,which is attached to the linking -NH'-"-;'-g'roup at the 4-position; andwhich may be iurther' substituted in the 6'-'15osition by a lowtalkylgroup, Q stands for a 'quinoline-nueleiis whi'ch'is substituted in theii-position by anamih'o' or lower alkylai'nino-group and whic'liirlai be'f uffthei' substituted by a lower alkylgroup on roups and which bearsthe linking -NH--=- group'jin the 6-position and wherein the 'syn 1bolsq indi cate that the preceding'fhucleL-P' and Q' res'p' etively, arepresent in the fdrmot their' 'quaternary salts.

According to the invention the said compounds are manufactured by aprocess which orn-firises subjecting to the action" of 'a nionia loweralkylarnino" a,- conipound if-the farmma wherein the syrnbols qqindie'ate t at me campound is a diquatrnary saitsw iicna fiesahequaternaiy group on the q'uirioline nucleus and the other on thepyriinidineniieleiis, and; wh in X and Y stand for amino '01 loweralkylain groups or for the groups -S-R. or in R stands for a hjdrocai'hdniafii'cf firovided that of X and Y at least one is -S R R, andwherein A stands fc'ir 61" a lower alkyl group and B stands forhydi'dgehdi a 'ldw er alliyl group. 7 I H The resctionmay convenientlybe cari'ied but by heating the reactants together in a llduid solvent ordiluent. The heating is advisedly carried out in a'closed vessel; h U

The compounds made aeeording to the present invention may also be madeby the'processes described in'the following co-pe'ndin'g United King IThe invention is iuiistratedjbut n t By the following ezilfiples inwhich the parts are b'y weight.

(c1. 2s0--2ss.4)

hour. 'th nit'oo edand extracted with water and 150" earner sodiumiodide are added to theexti act, which is then filte 'ed. The residueconsists of 4-chloro-2- ineth'ylthi'o' 6 methylbyrimidine 1=methi6dideof MQP 185 6. meeempm 1&9- Darts of thissubstaneeared-issolvedinl5artsof hot water and the'soluti'on is addedto-a not solution of 126 parts of4': fi di am inoquinaldine rhethochloride hydrochloride in 12 parts ofwater "and the-mixture is boiled for -45-minutes Ibis then cooled andfilteredand the seli'd'is-dissolved in 30 partsof water and 4 parts ofsodium i'odide' 'aie added to the solution "which is then filtered4=amino=6-"(2-n1ethylthid -6 methylpyrirnidyl 4'*amino)quina1d1ne1:-I'-dimethiodide' is db tained and crystallised from water; M. R 253255 C; -(deeoinp.)'.

Ehidifitle 2 i-parts of 6--(2 amino=6'-methylpyrimidylg lamino)-4;methoxyquinaldin e 1 z'lf r-dimethiodide, 4 parts of-ammoniumchloride and: parts of a solutionyotammonia in ethyl alcohol; saturatedbelow 5? Q, are heated together in apl'osed vessel; at;--140 Ct for 6hours. The vessel isthen cooled and opened The excess ammonia is drivenby bo l ne- The; re du s dqQcW 39, Pa ts of water? w ic h tpe lqrieaedis asleed in amount sufil'cient togive a neutral suspension. ishieated"a solution is ohtained 10 parts ofsod'i'um iodide are; then ad ed t6 hesolution which is thn filtered; thejsohdisci'ys tallis'ed froth waterand '-amind-t-Q ainino 6'inethylpyrimidyLf-amino) quinaldine' 1-:1'-'dimethiodide is obtained in the form of creamcoloured crystals, M. P.312313 C. (decomp.). This product may be converted into 4-amino-6-(2'amino-6'-methylpyrimidyl-4-amino) quinaldine 1:l-dimethochloride, M.P. 316-317" C. (decomp.) by dissolving 3 parts of it in 200 parts ofboiling water and adding to the solution 35 parts of sodium chloride,filtering off the precipitated solid and crystallising it from water.

The starting material used in the process of this example may beobtained as follows:

30 parts of 6-acetylamino4-methoxyquinaldine, 80 parts of nitrobenzene,60 parts of toluene and 20 parts of dimethyl sulphate are stirred andheated together at 90-100 C. for 90 minutes.

80. parts of water are then added and the aqueous layer is separated,heated to 70 C. and a solution of 30 parts of sodium iodide in 40 partsof water is added to it. The mixture is cooled and filtered and thesolid is washed with ethyl alcohol and then crystallised from water. Theproduct is G-acetylamino4-methoxyquinaldine methiodide monohydrate,M.,P. 305- 307 C. (decomp.). 30 parts of this substance, 42 parts ofconcentrated hydrochloric acid and 200 parts of water are boiled underreflux for 30 minutes, then 200 parts of water are added, the mixture isheated to 90-95 C. and sodium carbonate is then added until the pH ofthe mixture is 3. 24 parts of 4 chloro 2 amino-6-methylpyrimidine 1-methiodide are then added and the mixture is heated at 90-95 C. for 15minutes, filtered at 80 C. and the residue is washed with 0.1N-hydrochloric acid, then with water until the washings are no longeracid to Congo red. It is then dissolved in 1000 parts .of boiling waterand a solution of 100 parts of sodium iodide in 100 parts of hot wateris added. The mixture is filtered at 90 C. and the solid is washed withwater. There is obtained 6-(2amino-6-methylpyrimidyl-4- amino)4-methoxyquinaldine 1:1'-dimethiodide as its hydrate, M. P. 306 C.

v Example 3 5 parts of 6-(2-amino-6-methylpyrimidyl-4- amino) 4methylthioquinaldine 1:l.dimethiodide, 10 parts of ammonium chloride and250 parts of a solution of ammonia in ethyl alcohol, saturated below 5C., are heated together in a closed vessel for 6 hours at 130 C. Thevessel is then cooled and the contents stirred with 500 parts of waterand hydrochloric acid to the point of neutrality. The mixture is thenfiltered and the solid residue is dissolved in 500 parts of water, thesolution is treated with carbon and filtered and to the filtrate thereis added at 70'- 80 C., 30% aqueoussodium chloride solution in excess.It is then filtered while still hot and there is obtained 4 amino-6 (2amino 6- methylpyrimidyl 4 amino) quinaldine 1:1- di'methochloride of M.P. 3 1'6-317 C. (decomp.). The starting material usedin the processofthis example may be obtained as follows:

23.6 parts of 4' chloro 6 acetylaminoquinaldine, 14 parts of the sodiummethyl mercaptide and 100 parts of ethyl alcohol are heated togetherunder-"reflux for 3 hours and then filtered hot. The filtrate isevaporated to half its original volume and then mixed with 200 parts ofwater and filtered. The solid is crystallised 'from etliyl al cohol and.is 6acetylamino-4methylthioquin aldine, M. P. 220-221 C. 16.3 parts ofthis substance, 163 parts of nitrobenzene and 8.6 parts of dimethylsulphate are heated together at 90- 95 C. for 20 minutes, cooled andtreated with 500 parts of water. The aqueous layer is separated and asolution of 50 parts of sodium iodide in 50 parts of water is added toit. It is then filtered and the solid is washedwith ethyl alcohol andcrystallised from water. 6 acetylamino 4- methylthioquinaldinemethiodide, M. P. 279 C. is obtained, one part of which is boiled with10 parts of concentrated hydrochloric acid and 200 parts of water forone hour. The mixture is cooled and filtered. The solid is dissolved in1000 parts of boiling water, sodium iodide is added and the mixture isfiltered hot. 6-amino-4-methylthioquinaldine methiodide is obtained, M.P. 320 1 part of this substance, 300 parts of water and 4.5 parts of4chloro-2-amino-6-methylpyrimidine l-methiodide are heated together forminutes, the mixture is cooled and filtered. The solid is washed withmethyl alcohol and is 6- (2' amino-6' methylpyrimidyl-4'-amino)4-methylthioquinaldine 1:1'-dimethiodide of M. P. 300-302 C. (decomp.).

Example 4 3.2 parts of 6-(2amino-G'-methylpyrimidyl- 4'amino)4-methoxyquinaldine 1:1-dimethiodide (made as described in Example2), 3 parts of methylamine hydrochloride, 8 parts of ethanol and 10parts of methylamine are heated together in a closed vessel for 6 hoursat 140 C. The vessel is then cooled and the contents are mixed with 200partsof water and the mixture is neutralised with hydrochloric acid. Itis then filtered and the residual solid is dissolved in 300 parts ofboiling Water. To the solution there are added 20 parts of sodium iodidedissolved in 30 parts of water. It is then filtered hot. There isobtained 4 methylamino 6 (2' amino 6- methylpyrimidyl 4-amino)quinaldine 1:1- dimethiodide of M. P. 2945 C. (decomp.).

Example 5 2 parts of 6 (2' methylthio 6 methylprimidyl4'-amino)4-methoxyquinaldine 1:1- dimethiodide, 2 parts of ammoniumchloride and 20 parts of a solution of ammonia in ethanol saturated at50 C. are heated in a closed vessel at C. for 6 hours. The vessel 'isthen cooled and then contents are mixed with 300 parts of water and themixture is neutralised' with hydrochloric acid. It is then filtered andthe residual solid is dissolved in 100 parts of boiling water. Thesolution is treated with carbon and filtered. The filtrate is treated at70-80 C. with 30% aqueous sodium chloride solution and filtered. Thesolid residue consists of 4-amino-6-(2- amino 6' methylpyrimidyl4-amino)-quinaldine 1:1'-dimethochloride of M. P. 316-317 C. (decomp.).

7 The starting material used in the process of the above example may beobtained as follows:

Hot solutions of 4.4 parts of 6-amino-4-methoxyquinaldine methochloridehydrochloride monohydrate in 100 parts of water and of 4.75 parts of 4-chloro2methylthio6-methylpyrimidine l-methiodide in 45 parts of waterare mixed and boiled together under reflux for 1 hour and then filtered.The solid is washed with water and dissolved in 200 parts of water. Tothe solution there is added a solution of 6 partsof sodium iodide in 50parts of hot water. The mixture is cooled and filtered and the solid iscrystallised from water. There is obtained 6-(2-methylthio- 6'methylpyrimidyl 4' aamino) 4 methoxyquinaldine l:1'-dimethiodidemonohydrate, M. P. 213 C. (decomp.).

are ef'lq lpaits o anh d o fi-eq -h wxy i n line 5 rts Q nitrolie e eand sa s *beziz ne is s irre d never t 165 s le end reated w 8- Pari dihiiis il hai Th mix ure is stirred t 4; .55 C- n sh ws-t o d a xt ae dwith 22 5' parts orwa-ter and the extract is'brou ht to yadditionbfeodiumhydroxide. -It is i01 d' 1 i 2fe-2;0%eq ous solution-ofsodiunrhydroxide are-added. The mixture is heated for il ourat 70 C.,cooled and filtered. 6-acetylarnino 4-ethoxyquinoline, M. P. is b i-e d.Ii-is e u d ref .ex 55 oia mixture ofequal parts of wa- 1 n i o 1 .i isoo ed ma a a i e by o .e ie us s idium hydro d n amate r th r'q uct m n-ihr 'noline..M 11781-170 C 1.95 parts of 4.- inop' 'mi dine and 30parts of N- ecider heat d i s he r 1 our. sauce of aqueous sodium l d l'-a Q uinolinehydrate isfiltered ofif and crysma efequel Pa f methyl.andwater hasIlVLfP'. 2251-225 0. This and 2.8 parts. of ii-ar erieandPar s .The m xture is cooled and e r su h te er -add d to ed @3 ore hourcoole W '1 use wash d. i hn t e ze e a d ethyl acetate and'drie'd at 60C. 'It i thendi l edi 1 a rts f Wat r -and t the fi 'd i t isc t d atheats with 45 artsofnitrob solution is added a solution of '6 parts of.sodium iodide in 30 parts of water. The mixture is fil- FP LWBi he so idi l allised Hen; water.- 6-(2'-amino-pyrimidyl 4 amino) 4 ethoxyquinoline 1:1-dimethiodide monohydrate is obtained, M. P. 324 C.(decomp.).

Ewample. 7

6 parts of 6-(2':aminopyrimidyl-4-amino) -4- ethoxyquinaldine lzl'dimethiodide, 6 parts of ammonium chloride and 80 parts of a solutionaminopyrimidyl 4' aminolquinaldine 1:.1' 1.111:- methiodide monohydrate,M. P. 300-301 C. v(decomp.) is obtained.

The starting material used in theeprocess of this example may beobtained asofollows:

A mixture of 4.3 parts of LG-acetylamino-dhydroxyquinaldine, 30 parts ofnitrobenzene and 10 parts of benzene is heate to 165, co d and 3.9;parts of diethyl sulphate are added to it. It is then stirred and heatedat 145-155 vC. for v4 hours, cooled and extraeted with 90 parts ofwater. The extract is made of pH ,6 by addition thereto of aqueoussodium hydroxide andis warmedto 65-70 C. 5 parts of a solution of sodiumhydroxide are then added and the mixture is maintained at 65- 70 C. for15 minutes. It is then cooled and filtered and the solid iscrystallisedfrom aqueous ethyl alcohol. There is obtained 16-acetylamino-4-ethoxyquinaldine, M. P. 218 C. This is heated underreflux with .an excess Of a mixture of equal parts of water andconcentrated hydrochloric acid for 1 hour and there is thus obtained6-amino-4 ethoxyquinaldine, M.-P. 1A4- 145 C. A mixture of 1 part ofthis 6-amino-4- eth0xyquina1dine, 0.65. part of.4-chloro-2,-ami-nopyrimidine and 10 parts of N-hydrochloricacid isboiled. for 1 hour, cooled and made alkaline by addition of aqueoussodium hydroxide. 6-.(2Q aminopyrimidyll'-amino)-4 ethoxyquinaldinemonohydrate is filtered and crystallised from aqueous methyl alcohol. Ithas M. P. 217-219 C. 1.9 parts of this product: are .idehydrated: withparts of nitrobenzeneand-z 20 parts ofbenzeneuto 609C. and. Lamar-tenetdimethylnsulphateare added: to the cooledmixture; Whichisthen stirredandheatedtat l05-ll5f C.'.f0l-4 hours, cooledand filtered. The. solid.is 1 washed with nitrobenzehe and. ethylacetateanddried. 'Itvis. thendissolved M200 .partsof: hotwater andstothesolution there istaddeda hotsolution .of-4 parts of sodiumiodide iniil parts .ofwater. The solutionis then filtered andthez filtrate is cooled and:.6-(ZR-.aminopyrimidyl-l' -amino .-=4-1ethoxyquinaldine 1 :1 --.dimethr.iodide .dihydrate is filtered off. and crystallised fromiwater. It has.M.'P..342.C. (decomo).

10 parts of 6-(2'-Inethylamino-6'-methy1py- .0 rimidyl 4'-amino)--4--=phenoxyquinaldine 1:1-

iusihi did .iwmq iumehlqri e a made by sa r tin ethyl ii 6v hea d t h ri 6 hours, cooled The mixture lor c, a id n 4.00 parts of .15 Parisofpsqdium Wa r add d The m t r efil er te i c o ed a d str te li .ii War issue $9.5? oil birs-il f A ialusedi he aboye exame and parts of phe eed o r-3v hours at w i8Q+ 9Q=Q=e i a sem eoold an d. dded crystallisedfrom water and Aeami'nQ-jG-QM hol. The mixture is cooled and filtered.6-acetylamino 4' phenoxyquinaldine hydrate is obtained. 19.6 parts ofthis substance is dehydrated and heated at 90-95 C. for 2 hours with 209parts of nitrobenzene and 10.1 parts of dimethyl sulphate. The mixtureis then cooled and filtered and the solid is boiled for 30 minutes with150 parts of a mixture of equal parts of water and concentratedhydrochloric acid, filtered hot and cooled and again filtered. The solidproduct is 6-amino 4 phenoxyquinaldine methochloride hydrochloride whichis crystallised from a mixture of equal parts of water and concentratedhydrochloric acid. It has M. P. 270 C. (decomp.). A-solution of 2.9parts of this 6-amino-4-phenoxyquinaldine methochloride hydrochloride in100 parts of hot water is mixed with a solution of 2.55 parts of4-chloro-2-methylamino-6-methylpyrimidine l-methiodide in 25 parts ofhot water and the mixture is boiled under reflux for 75 minutes. It isthen cooled and filtered. The solid is washed with cold water and thendissolved in 150 parts of hot water and to the solution a hot solutionof 6.5 parts of sodium iodide in 50 parts of Water is added. The mixtureis filtered and the solid product is crystallised from water to give 6(2' methylamino 6 methylpyrimidyl-4-amino) -4-phenoxyquinaldine 1: 1'-dimethiodide dihydrate, M. P. 268-269 C. (decomp.).

Example 9 1.8 parts of 4-methoxy-6-(2'-methylthio-6'- methylpyrimidyl 4'amino) quinaldine 1:1-dimethiodide, 12 parts of ethylamine and 12 partsof ethyl alcohol are heated together in a closed vessel at 130-140 C.for 6 hours. The mixture is cooled and poured into 120 parts of waterand hydrochloric acid is added until the mixture is just acid. It isthen filtered and the solid is washed with water and dissolved in 120parts of boiling water and to the solution a solution of 2.5 parts ofsodium iodide in 10 parts of water is added. The mixture is filtered andthe filtrate is cooled and filtered and the solid is crystallised fromwater to give 6-(2-ethylamino-6-methylpyrimidyl-4-amino) 4ethylaminoquinaldine 1:1- dimethiodide monohydrate, M. P. 319 C.(decomp.)

Example 10 1.35 parts of 6-(2'-amino-6-methylpyrimidyl- 4'-amino)-4-benzylthioquinaldine 1:1 dimethiodide, 1.35 parts of ammoniumchloride and 13.5 parts of a solution made by saturating ethyl alcoholwith ammonia at C. are heated together in a closed vessel at 130-140 C.for 6 hours. The mixture is then cooled and poured into 60 parts ofwater and hydrochloric acid is added to the mixture until just acid. Itis then filtered, the solid is washed with water and dissolved in 37.5parts of boiling water and to the mixture is added a solution of 2.25parts of sodium iodide in 7.5 parts of water. The mixture is filteredhot, cooled and again filtered. The solid is crystallised from water togive 4-amino-6-(2-amino- 6'-methylpyrimidyl-4' amino)quinaldine 1:1-dimethiodide dihydrate, M. P. 314-315 C.

The starting material used in this example may be obtained as follows:

6.2 parts of benzyl mercaptan are added to 25 parts of ethyl alcohol inwhich 1.15 parts of sodium have been dissolved. To the solution 7.05parts of 4-chloro-fi-acetylaminoquinaldine are added and the mixture isstirred and boiled under reflux for 3% hours and then filtered hot.

The filtrate is cooled and again filtered and the solid is 6 acetylamino4 benzylthioquinaldine which is crystallised from methyl alcohol andthen has M. P. 213 C. 19.2 parts of this6-acetylamino-4-benzylthioquinaldine, 9.45 parts of dimethyl sulphateand 200 parts of nitrobenzene are heated together for 2 hours at -95 C.The mixture is then cooled and filtered and the solid is washed withnitrobenzene and then with ethyl acetate. It is then boiled for 1 hourwith a mixture of 600 parts oi. water and parts of concentratedhydrochloric acid, cooled and filtered. The solid is crystallised fromwater and B-acetylamino-4-benzylthioquinaldine methochloride d1- hydrateis obtained, M. P. 227-229 C. Hot solutions of 7.5 parts of this6-acetylamino-4-benzylthioquinaldine methochloride in 1100 parts ofwater and of 6.4 parts of 4-chloro-2-amino-6- methylpyrimidinel-methiodide in 70 parts of water and 22.5 parts of N-hydrochloric acidare mixed and the mixture is boiled under reflux for one hour. It isthen cooled and filtered and the solid is washed with acetone anddissolved in 600 parts of hot water. A hot solution of 20 parts ofsodium iodide in 60 parts of water is added to this solution which isthen cooled and filtered and the solid is crystallised from water. 6 (2amino-6'-methylpyrimidyl-4'-amino) -4- benzylthioquinaldine 1:1dimethiodide dihydrate, M. P. 232 C. (decomp.) is obtained.

Example 11 1.15 parts of anhydrous 6-(2-amino-6- methylpyrimidyl-4amino) 4 methoxyquinaldine 1:3-dimethiodide, 1.15 parts of ammoniumchloride and 12 parts of a solution prepared by saturating ethyl alcoholwith ammonia at 0 C. are heated in a closed vessel at l30'-l40 C. for 6hours. The mixture is cooled and poured into 40 parts of water and tothe mixture hydrochloric acid is added until it is just acid. It is thenfiltered and to the filtrate is added first a solution of 4 parts ofsodium iodide in 5 parts of water and then aqueous sodium carbonateuntil it is alkaline to Brilliant Yellow. It is then filtered and thesolid is crystallised from water to give 4 amino 6-(2-amino-3:6'-dimethyldihydropyrimidyl-4 -amino) quinaldine l-methiodide M. P. 316C. (decomp.). This substance may be recrystallised from a 4% solution ofsodium iodide in water containing sufficient hydrochloric acid to give apH of 3 and 4-amino-6-(2'- amino 6 methylpyrimidyl-l' amino) quinaldine1:3-dimethiodide, M. P. 290 C. (decomp.) is obtained.

46 parts of B-acetylamino-4-methoxyquinaldine are heated at 90-95 C. for90 minutes with 31.5 parts of dimethyl sulphate and 350 parts ofnitrobenzene. The mixture is cooled and filtered and the solid is washedwith nitrobenzene and then with ethyl acetate. It is then boiled underreflux for 30 minutes with a mixture of parts of water and 300 parts ofconcentrated hydrochloric acid and then filtered. 1500 parts of ace toneare added to the filtrate and 6-amino-4-1 methoxyquinaldinemethochloride hydrochloride monohydrate is filtered 011 and crystallisedfrom a mixture of acetone and ZN-hydrochloric acid.

It has M. P. 280-281 C. (decomp.). This product is converted to themethochloride, M. P. 231 C.

(decomn) by dissolving it in water, and addingto the solution an excessof sodium hydroxide followed by sodium chloride. It is crystallised frommethyl alcohol. A mixture of 2.4 parts of fi-amino-4-methoxyquinaldinemethochloride, 1.9 parts rimidyl-4-amino) 4-methoxyquinaldine 1:3-dimethiodide, M. P. 245 C. (decomp) is obtained.

Example 12 A mixture of 0.92 part of 6-(2-methylthio-6-methylpyrimidyl-4 amino) 4 methoxyquinaldine 1:1'-dimethiodide, 6 partsof ethylamine and 8 parts of toluene is heated in a closed vessel at130-1l0 C. for 6 hours, then cooled and filtered. The solid is washedwith ethyl acetate, dried and dissolved in 65 parts of boiling watercontaining sufficient hydrochloric acid to give a pH of 4. A solution of1.5 parts of sodium iodide in 5 parts of water is added to the solutionand the mixture is filtered hot. The filtrate is cooled and filtered andthe solid is crystallised from water. 6-(2- ethylamino-6methylpyrimidyl4'-amino) 4- ethylaminoquinaldine l 1 -dimethiodide monohydrate of M. P.317 C. (decompl) is obtained.

Example 13 A mixture of 0.92 part of 6-(2-methy1thio-6 methylpyrimidyl4'-amino) 4-methoxyquinaldine 1:1'"-dimethiodide, 6 parts of ethylamineand 8 parts of anisole is heated in a closed vessel at 130140 C. for 6hours. It is then cooled and filtered and the solid is washed with ethylacetate in 65 parts of boiling water containing sufficient hydrochloricacid to give a pH of 4. A solution of 1.5 parts of sodium iodide in 5parts of water is then added and the mixture is boiled and filtered hot.The filtrate is cooled and 6-(2'-ethylamino-6methylpyrimidyl-4'amino)4-ethylaminoquinaldine 1:1-dimethiodide is filtered off and crystallisedfrom water. It has M. P. 318 C. (decomp.).

We claim:

1. Process for the manufacture of diquaternary salts ofpyrimidylaminoquinolines having the general formula:

IITH R NH mR Ra I V wherein R is a radical from the group consisting oflower alkyl and NH alkyl; R1 and R2 are radicals from the groupconsisting of hydrogen and lower alkyl without R1 and R2 both beingsimultaneously hydrogen atoms; and R3 is a radical from the groupconsisting of hydrogen and lower alkyl, which comprises reacting adiquaternary salt of a compound of the general formula:

wherein one of the radicals X and Y is a radical from the groupconsisting of S alkyl and -0 alkyl, and the other is a radical from thegroup consisting of S alkyl, 0 alkyl, NI-Iz and NH alkyl, and R and R3have the significance above indicated, with a compound from the groupconsisting of ammonia and lower mono-alkylamines.

2. A process as claimed in claim 1 wherein said reaction is broughtabout by heating the reactants together in a solvent.

GILBERT JOSEPH STACEY. HENRY WILLIAM THOMPSON. CHARLES HENRY VASEY.MURIEL RUTH CURD,

Eaecutria: of the Estate of Francis Henry Swinden Curd, Deceased.

No references cited.

1. PROCESS FOR THE MANUFACTURE OF DIQUATERNARY SALTS OFPYRIMIDYLAMINOQUINOLINES HAVING THE GENERAL FORMULA: